tbuckley/cabot-search huggingface dataset:
Abstract 6438: Next-generation pan-cancer immunotherapy with patient-derived APC
Authors: Zhen Bian, Lei Shi, Yuan Liu, harry Stylli
Journal: Cancer Research (2023)

Abstract Harnessing phagocytic antigen presenting cells (APC) and tumor neoantigen-specific T cells represent the ultimate power of immunotherapy against cancer. The promises of phagocytic APCs lie in their abilities of not only initiating phagocytosis towards cancer cells (to “eat off” tumor) but also, through immunogenic antigen presentation, activating neoantigen-specific Tcells that systemically and durably eliminate cancer cells, as well as the establishment of a long-lasting cellular and hormonal immunity that prevents tumor recurrence. However, the efforts of developing APCs -based therapy have been hindered by the current lack of technology that robustly produce APCs from cancer patients, as none of the traditional methods for differentiating DC or macrophage APCs are effective for cancer patients. Through a proprietary process, we have created a unique reagent combo that enables robust differentiation of cancer patients’ peripheral monocytes (cMo) to be potent APC, termed κAPC. κAPC display a unique gene expression profile, separating from classical DC or macrophage, and profound proinflammatory phenotype with enhanced phagocytic capability and elevated immunogenic antigen presentation machinery. In both in vitro and in vivo settings, κAPC demonstrate direct uptake of tumor antigens and presentation to T cells, the latter leading to activation and large expansion of multi-targeting, polyclonal tumor-specific CD4 and CD8 T populations - termed NeoT- from circulating and tumor-infiltrating lymphocytes. Theexpanded CD8 NeoT are highly tumoricidal and once adoptively transferred in vivo, potently eliminated late-stage metastatic solid tumors, whereas CD4 NeoT contribute to immune memory and repolarize a proinflammatory TME favorable for tumor elimination. Key words: κAPC, NeoT, NeoT adoptive cell therapy, κAPC-based cancer vaccine, combination therapies Citation Format: Zhen Bian, Lei Shi, Yuan Liu, harry Stylli. Next-generation pan-cancer immunotherapy with patient-derived APC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6438.
Multicenter randomized phase III trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC) as perioperative chemotherapy for muscle-invasive bladder cancer (MIBC): Overall survival (OS) data at 5 years in the GETUG/AFU V05 VESPER trial.
Authors: Christian Pfister, Gwenaelle Gravis, Aude Flechon, Christine Chevreau, Hakim Mahammedi, Brigitte Laguerre, Aline Guillot, Florence Joly, Yves Allory, Valentin Harter, Stephane Culine
Journal: Journal of Clinical Oncology (2023)

LBA4507 Background: The optimal perioperative chemotherapy for patients (pts) with muscle-invasive bladder cancer remains open to discussion. The primary endpoint of the VESPER trial (NCT 018 12369) was previously reported with dd-MVAC improved-3 years PFS over GC schedule. In the neoadjuvant group, a better bladder local control and significant difference on 3y-PFS was observed in the dd-MVAC arm (p=0.025). Patients and Methods: Between February 2013 and February 2018, 500 pts were randomized in 28 French centers and received either 4 cycles of GC every 3 weeks or 6 cycles of dd-MVAC every 2 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). We report the final analysis of the VESPER phase III trial with the overall survival (OS) data after 5 years of follow-up from randomization. Results: 437 pts (88%) received neoadjuvant chemotherapy, 60% of patients received the planned 6 cycles in the dd-MVAC arm, 84% received 4 cycles in the GC arm, thereafter 91% and 90% of patients underwent surgery, respectively. Final median of follow-up was 5 years and 3 months and 190 deaths were reported within 5 years of follow-up. OS at 5 years was improved in the dd-MVAC arm (64% vs 56%, HR=0.77 (95% CI, 0.58-1.03), p=0.078), as was also disease-specific survival (DSS) (5-year rate: 72% vs 59%, HR=0.63 (95% CI, 0.46-0.86), p=0.004). The main cause of death was bladder cancer progression (83%), other causes included cardio-vascular events (4.2%), toxic deaths (2.1%), second cancers (2.1%), others (4.7%) and undocumented deaths (4.2%). In the neoadjuvant group, OS was significantly superior in the dd-MVAC arm (5-year rate: 66% vs 57%, HR=0.71 (95% CI, 0.52-0.97), p=0.032) as well as DSS (5-year rate: 75% vs 60%, HR=0.56 (95% CI, 0.39-0.80), p=0.001). In the adjuvant group, the results were not conclusive due to the limited sample size (n=56).Conclusions: Dose-dense MVAC provided a better OS at 5 years and improved significantly DSS over GC in the peri-operative setting of MIBC. Clinical trial information: NCT01812369 .
Abstract 6032: Exploiting metabolic vulnerabilities of ovarian cancer with upregulated succinate dehydrogenase
Authors: Lin Wang, Magdalena Bulicz, Patryk Mucha, Michael Kinter, Atul Pranay, Timothy M. Griffin, Benjamin F. Miller, Magdalena Bieniasz
Journal: Cancer Research (2023)

Abstract Ovarian cancer remains the deadliest of all gynecologic malignancies nationwide due to limited therapeutic options and chemotherapy resistance. The response to chemotherapy is substantially influenced by the high metabolic flexibility of ovarian cancer cells, which allows the cells to reprogram their metabolism and survive the treatment. Better understanding mechanisms regulating ovarian tumor metabolism could be exploited to develop new improved therapies. Our work demonstrated that the upregulation of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent (~20% of patients) in ovarian carcinoma and contributes to high energy tumor metabolism and cell survival. We observed that SDHA overexpressing ovarian cancer cells showed improved ability to survive and generate colonies in anchorage-independent conditions, which is an important feature of ovarian tumor cells surviving and spreading in peritoneal fluid (ascites). Proteomics data revealed that the SDHA overexpressing tumor cells showed reduced levels of proteins promoting anaerobic glycolysis (LDHA and HIF1α), and increased levels of mitochondrial pyruvate carrier (MPC) proteins. In addition, our tracer-based metabolomics data revealed that the elevated SDHA stimulates glutaminolysis by increasing mitochondrial glutamine supply fueling the TCA cycle with essential metabolites. We also demonstrated that the overexpression of SDHA is associated with a significant increase of OXPHOS and ATP production rate. Further, we reasoned that the SDHA overexpressing tumor cells could be particularly vulnerable to drugs disrupting glucose and/or glutamine metabolism. We performed a drug screening and identified an anti-metabolic compound shikonin known to disrupt glucose and amino acid metabolism. In in vitro studies, shikonin exhibited a profound anti-tumor efficacy and selectivity towards SDHA overexpressing tumor cells superior to that observed with chemotherapy. Importantly, our in vivo study validated the in vitro observations, and showed that shikonin is highly effective in suppressing SDHA overexpressing patient-derived tumor growth. In summary, the unique metabolic state of ovarian cancer associated with SDHA amplification could be successfully targetable offering a potential new treatment strategy for ovarian cancer patients. Citation Format: Lin Wang, Magdalena Bulicz, Patryk Mucha, Michael Kinter, Atul Pranay, Timothy M. Griffin, Benjamin F. Miller, Magdalena Bieniasz. Exploiting metabolic vulnerabilities of ovarian cancer with upregulated succinate dehydrogenase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6032.
Abstract 6645: A systematic approach for detection of tumor genomic alterations which alter the immune microenvironment
Authors: Raven Vella, Emily L. Hoskins, Julie W. Reeser, Michele R. Wing, Eric Samorodnitsky, Anoosha Paruchuri, Amy Smith, Leah Stein, Thuy Dao, Zachary Risch, Sameek Roychowdhury
Journal: Cancer Research (2023)

Abstract Objectives: Leveraging whole exome and transcriptome data from large cancer datasets, we sought to develop a computational approach to nominate candidate genomic alterations that are associated with hot or cold tumor. We anticipate this tool will identify candidate novel drug targets and biomarkers for immunotherapy in cancer. Methods: The user selects a gene of interest (GOI) as input for the pipeline. The pipeline searches TCGA (The Cancer Genome Atlas) mutation and structural variant outputs to collect hits in the gene of interest. Each sample with an alteration in the GOI is annotated with the alteration’s predicted biological function (loss-of-function or LOF vs gain-of-function or GOF) using gene set enrichment analysis and pathway analysis from RNA sequencing. After annotating by sample, the alterations themselves are scored and recorded. Next, Quantiseq and Trust4 are employed to estimate features of the immune microenvironment in both the LOF and GOF samples. These results along with cancer type distributions, genomic position maps, and oncoplots are delivered to the user for further investigation. We are creating an online application to provide these results to the public. Simultaneously, a command line tool is being developed for application to any data source. Results: We will present findings for the pipeline using positive controls including genomic alterations in ADAR, MTAP, IDH1, and CD274 (PD-L1). Preliminarily, we identified candidate GOF mutations (n=81) in PD-L1 that have inflamed tumor immune microenvironments like those of samples with known GOF structural variations in PD-L1. These samples have an overall “hot” immune microenvironment with significantly (p&amp;lt;.05) increased M1 macrophages, increased expression of IFN-gamma, and decreased M2 macrophages. Conclusion: Currently there are no systematic approaches to interrogate individual genomic alterations and their association with an altered immune microenvironment. Our approach is pragmatic for any gene of interest, can be applied to any database, and identifies clinically actionable targets. This approach will identify heretofore unstudied connections between genomic alterations and immune microenvironment and support personalized drug development strategies in immuno-oncology. Citation Format: Raven Vella, Emily L. Hoskins, Julie W. Reeser, Michele R. Wing, Eric Samorodnitsky, Anoosha Paruchuri, Amy Smith, Leah Stein, Thuy Dao, Zachary Risch, Sameek Roychowdhury. A systematic approach for detection of tumor genomic alterations which alter the immune microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6645.
Abstract 6440: Targeting TCTP reverses the multi-malignant phenotypes of immune-refractory tumor cells
Authors: Hyo-Jung Lee, Tae Woo Kim
Journal: Cancer Research (2023)

Abstract Cancer immunotherapy, particularly T cell-mediated therapy such as immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT), has emerged as a potentially powerful approach to cancer treatment. However, immunotherapeutic resistance limits its clinical success by disrupting one or more steps of the cancer immunity cycle. In addition, multi-malignant phenotypes of immune-refractory tumor cells are also one of the major causes result poor prognosis of patients. Therefore, identifying the immune-resistance and multi-malignant factor, which not only can be targeted by clinically available medicines it can also be a prognostic marker, is needed ideally. Here, we identified TCTP as a novel factor conferring multi-malignant phenotypes of immune-refractory tumor cells. We discovered a crucial role of TCTP at the crossroads between multi-malignant tumor cells and the anti-cancer immunity system by demonstrating that TCTPhigh tumor cells enriched by immune selection pressure drive immune-refractory phenotypes. Importantly, the levels of TCTP within the tumors significantly correlated with the clinical outcome of anti-PD-L1 therapy, which demonstrate TCTP as a prognostic marker in the case of clinical trials. Furthermore, targeting TCTP by clinical available drug enhanced the response to T cell-mediated therapy including ICB and ACT. Thus, our findings emphasize that TCTP could be a both a valid target a prognostic marker providing a framework for patient selection to apply combined therapy of T cell-mediated therapy with TCTP-targeting agents. Citation Format: Hyo-Jung Lee, Tae Woo Kim. Targeting TCTP reverses the multi-malignant phenotypes of immune-refractory tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6440.
Abstract 54: Regulation of luminal epithelial cell identity in the pre-tumorigenic mammary gland
Authors: Jerrica Breindel, Kayla M. Gross, Charlotte Kuperwasser
Journal: Cancer Research (2023)

Abstract The transcription factor MYC is frequently altered in a large portion of human breast cancers; the gene is amplified in ~15% of breast cancers and overexpressed in another 30-50%. Mouse mammary tumor models driven by overexpression of MYC, such as MMTV-Myc, also exhibit a rapid onset and high frequency of mammary tumors indicating that MYC overexpression plays an important role in driving breast carcinogenesis. However, the role of MYC in breast cancer initiation and subtype determination is not well understood. In the normal mammary gland, MYC is a critical regulator of and is essential for alveolar luminal epithelial cell differentiation during pregnancy. Aberrant MYC expression can promote improper alveolar development and milk production and is a potent inducer of cellular proliferation. Based on these known functions of MYC during development, we hypothesized that its overexpression may induce early changes in epithelial cell differentiation leading to pre-tumorigenic shifts in cell lineages that contribute to the formation of luminal breast tumors. To investigate this, we analyzed the mammary glands of MMTV-Myc (MYC) mice prior to any signs of tumor formation. As early as 5 weeks of age, MYC overexpression led to alterations at both the histological and cellular levels. Interestingly, pre-tumorigenic MYC glands phenotypically resembled mid-pregnant glands of WT mice. Specifically, pre-tumorigenic MYC glands demonstrated budding along the mammary ducts and expansion of a Sca1−/CD49b− luminal epithelial cell subset not typically seen in nulliparous mice. RNA-seq was performed on luminal epithelial cells isolated from WT or pre-cancerous MYC mammary glands to define the luminal differentiation states upon MYC overexpression. While there was an overlap in twenty-nine genes that control milk production and cellular metabolism between pre-cancerous MYC luminal cells and those from mid-pregnant WT mice, luminal cells from MYC mice also exhibited a unique fingerprint of forty-one genes that overlap with cell states found in breast cancer. These uniquely expressed luminal cell genes may be important for MYC-regulated tumorigenesis. Ongoing and future experiments will investigate the role of specific MYC-target genes in mammary gland development versus tumor formation to clarify the role of MYC in these divergent processes. Citation Format: Jerrica Breindel, Kayla M. Gross, Charlotte Kuperwasser. Regulation of luminal epithelial cell identity in the pre-tumorigenic mammary gland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 54.
Abstract 5823: Uncovering the mechanisms of matrix metalloproteinase-3 (MMP-3) in the cisplatin resistance of ovarian cancer
Authors: Mariela Rivera-Serrano, Pablo E. Vivas-Mejia
Journal: Cancer Research (2023)

Abstract Seventy percent of women with ovarian cancer will develop chemotherapy-resistance to cisplatin. Regardless of the advancements in technology, mortality rates for ovarian cancer have declined only slightly in the last forty years, reiterating the need to generate novel treatment options targeting cisplatin resistance. In RNA-seq and microarrays experiments we observed that Matrix-metalloproteinase-3 (MMP3) was highly abundant in cisplatin-resistant when compared to cisplatin-sensitive cells. MMP3 is a member of the matrix metalloproteinases (MMPs) family of proteolytic enzymes, involved in the degradation of proteins in the extracellular matrix (ECM). Deregulation of MMPs alters the extracellular matrix and contributes to proliferation, invasion, and metastasis of cancerous cells. A typical MMP structure consists of a pro-domain, a catalytic, and a hemopexin domain. The catalytic domain is responsible for MMPs proteolytic activity, while the hemopexin domain contributes to substrate and ligand specificity. Inhibitors targeting the catalytic domain of MMPs were unsuccessful in clinical trials due to a lack of selectivity and specificity. When we used a chemical inhibitor, we did not observe reduced cell-proliferation or invasiveness. However, MMP3-targeted small interference RNA (siRNA) was able to reduce cell proliferation and invasive capabilities in cisplatin resistant ovarian cancer cells. Additionally, MMP3-targeted siRNA significantly reduced the sensitivity of ovarian cancer cells to cisplatin treatment. Cisplatin also increased MMP3 mRNA levels in ovarian cancer mice models and human cell lines. This evidence suggests that the MMP3 levels correlate with the sensitivity of ovarian cancer cells to cisplatin treatment. We hypothesize that the hemopexin domain will bind to proteins promoting cisplatin-resistance. We validated our expression profile studies at mRNA and protein levels via western blot, ELISA and qRT-PCR. Additionally, survival analysis using the Kaplan-Meier plotter database showed that ovarian cancer patients with low MMP3 levels live longer than patients with higher MMP3 levels. Furthermore, when we measured MMP3 activity, we observed decreased activity in cisplatin-resistant versus cisplatin-sensitive cells. Taken together, these data suggest that other domains of MMP3 (i.e., hemopexin domain) may have a function in the cisplatin resistance of ovarian cancer cells. Citation Format: Mariela Rivera-Serrano, Pablo E. Vivas-Mejia. Uncovering the mechanisms of matrix metalloproteinase-3 (MMP-3) in the cisplatin resistance of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5823.
Abstract 2733: TYMS as a novel target for AAV-based therapy
Authors: Vinod Vijayakurup, Benjamin Meyer, Akbar Nawab, Frederic J. Kaye, Maria V. Guijarro, Maria Zajac-Kaye
Journal: Cancer Research (2023)

Abstract The purpose of this study is to develop a strategy for treating pancreatic neuroendocrine tumor (PanNET) through blocking Thymidylate Synthase (TYMS or TS), a DNA metabolic enzyme. Elevated TYMS levels are frequently observed in human PanNET and are associated with worse prognosis and resistance to cytotoxic agents such as 5FU. Elevated TYMS levels directly promote tumorigenesis in vitro and ectopic expression of human TS (hTS) in transgenic mice promotes adenoma development in the endocrine pancreas in vivo. Pancreatic islet tumor formation in hTS transgenic mice occurred with a long latency period, suggesting that additional somatic events are required for PanNET formation and progression. Men1 was shown to be a frequent target for somatic mutation in PanNETs (44% have MEN1 mutations). Therefore, we established a new mouse model designated hTS/Men1-/-, where hTS is overexpressed in pancreatic islet cells carrying conditional Men1 null alleles. We observed that ectopic hTS cooperates with Men1 inactivation to significantly accelerate PanNET progression and shorten survival. Since traditional TYMS inhibitors, such as 5-FU, consistently induce tumor resistance and cannot cure advanced disease, we have now tested the ability of TS-shRNA delivered using adeno-associated viral (AAV) vectors as a pharmacological safe and effective anti-tumor strategy. We packaged TS shRNA under the mouse insulin promoter (mIP) for islet-cell specific expression using capsid optimized Y to F double mutant AAV (AAV8-2M) to generate viral particles of scAAV8-2M-mIP-GFP-hTS-shRNA. We treated hTS/Men1-/- mice with intraperitoneal (IP) injection (1x1011 viral genomes/mice). Treated and control mice were analyzed for PanNET progression, TYMS expression and survival. In addition, we tested a human PanNET tumor cell line (BON) that was isogenic with or without hTS expression for tumor formation in xenograft model. We confirmed sustained reduction of TYMS levels 3 weeks after IP delivery of AA8-2M-mIP-GFP-hTS-shRNA into PanNET tissues of hTS/Men1-/- mice. In addition, AA8-2M-mIP-GFP-hTS-shRNA delivery blocked PanNET tumor progression and enhanced the survival of treated mice as compared to vector controls. We also confirmed that TYMS knock-down in BON cells by hTS-shRNA reduced xenograft tumor growth as compared to non-specific shRNA controls. In conclusion, the ability of AAV-mediated TS shRNA to block PanNET tumor progression directly demonstrates the importance of elevated TYMS in tumorigenesis and offers a novel anti-cancer strategy. Citation Format: Vinod Vijayakurup, Benjamin Meyer, Akbar Nawab, Frederic J. Kaye, Maria V. Guijarro, Maria Zajac-Kaye. TYMS as a novel target for AAV-based therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2733.